The objectives of this program comprise a coordinated approach to the design, synthesis and pharmacological evaluation of chemotherapeutic agents. The guiding principles involve the recognition and exploitation of the structural, electronic and conformational relationships among molecular analogues. Validation of this approach to the design of chemotherapeutic agents will hopefully be of both practical and theoretical importance. Particular attention is being directed to the recognition of topological differences of evolutionary origin among enzymes promoting identical reactions in different tissues and organisms, and the exploitation of such differences as the basis for selective toxicity. The parincipal areas of interest are: 1. The design of compounds suitable for the mass treatment of infections with Schistosoma mansoni and S. japonicum. A number of nitroheterocyclic schistosomicides developed on the basis of these principles are being examined for acute as well as chronic toxicity prior to their clinical trial in man. 2. The development of structural, electronic and conformational analogues of amino acids particularly L-methionine that selectively inhibit the synthesis of S-adenosyl-L-methionine. Some of these agents possess antineoplastic, immunosuppressive and antiinfective properties. Efforts are being made to design analogues with increased therapeutic ratios and to seek other pharmacological applications. This program also supports operations of a Mass Spectrometer Center which serves a crucial supporting function for the synthesis of chemotherapeutic agents. The Mass Spectrometer Center furthermore is exploring both established and novel applications to problems in pharmacology and toxicology.